1. Field of the Invention
The present invention relates to a novel pyridine derivative and pyrimidine derivative, a salt thereof or a hydrate of the foregoing, having inhibitory activity against hepatocyte growth factor receptor, anti-tumor activity, inhibitory activity against angiogenesis, inhibitory activity against cancer metastasis or the like.
2. Related Background of the Invention
Overexpression of hepatocyte growth factor receptor (hereafter referred to as “HGFR”) is reported in various kinds of tumors such as a pancreatic cancer, a gastric cancer, a colorectal cancer, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a brain tumor or an ovarian cancer (non-patent document 1). HGFR expressed in these cancer cells is considered to be involved in cancer malignancy (aberrant growth, invasion or enhanced metastasis), because HGFR cause autophosphorylation of intracellular tyrosine kinase constitutively or upon stimulation by hepatocyte growth factor (hereafter referred to as HGF).
It is also reported that HGFR is expressed in vascular endothelial cells and is involved in tumor angiogenesis since HGF stimulates HGFR to facilitate proliferation and migration of vascular endothelial cells (non-patent document 2).
Furthermore, NK4, an antagonistic peptide for HGF, is reported to block HGF-HGFR signal to inhibit invasion of cancer cells and tumor angiogenesis (non-patent documents 3 and 4).
Therefore, a compound having inhibitory activity against HGFR is expected to be useful as an anti-tumor agent, an angiogenesis inhibitor or an inhibitor for cancer metastasis.
With regard to documents disclosing a low molecular weight compound having inhibitory activity against HGFR, the patent documents 1 to 11 are listed. However, the patent documents 1 and 2 disclose indolinone derivatives; the patent documents 3 and 4 disclose quinoline derivatives and quinazoline derivatives; the patent documents 5 and 6 disclose imidazole derivatives; the patent document 7 discloses aminopyridine derivatives and aminopyrazine derivatives; the patent document 8 discloses triazolopyrazine derivatives and imidazopyrazine derivatives; the patent document 9 discloses tetracyclic derivatives; the patent document 10 discloses triazolotriazine derivatives; the patent document 11 discloses pyrrole derivatives; therefore the compounds disclosed in these documents are obviously different in the structure from pyridine derivatives and pyrimidine derivatives according to the present invention.
The patent documents 12 and 13 disclose pyridine derivatives and pyrimidine derivatives similar in the structure to the compounds according to the present invention. The patent documents 12 and 13, however, do not disclose inhibitory activity against HGFR of the compounds disclosed in the patent documents 12 and 13 as well as the compounds according to the present invention.                [Patent document 1] WO 02/096361        [Patent document 2] WO 2005/005378        [Patent document 3] WO 03/000660        [Patent document 4] WO 2005/030140        [Patent document 5] WO 03/087026        [Patent document 6] WO 2005/040154        [Patent document 7] WO 2004/076412        [Patent document 8] WO 2005/004607        [Patent document 9] WO 2005/004808        [Patent document 10] WO 2005/010005        [Patent document 11] WO 2005/016920        [Patent document 12] WO 02/032872        [Patent document 13] WO 2005/005389        [Non-patent document 1] Oncology Reports, 5, 1013-1024 (1998)        [Non-patent document 2] Advances in Cancer Research, 67, 257-279 (1995)        [Non-patent document 3] British Journal of Cancer, 84, 864-873 (2001)        [Non-patent document 4] Cancer Sci., 94, 321-327 (2003)        